Enhancing the uptake of dextromethorphan in the CNS of rats by concomitant administration of the P-gp inhibitor verapamil

被引:26
|
作者
Marier, JF
Deschênes, JL
Hage, A
Seliniotakis, E
Gritsas, A
Flarakos, T
Beaudry, F
Vachon, P
机构
[1] Univ Montreal, Dept Vet Biomed, Fac Vet Med, Montreal, PQ J2S 7C6, Canada
[2] MDS Pharma Serv, Quebec City, PQ H4R 2N6, Canada
关键词
dextromethorphan; verapamil; CNS; dextrorphan; P-glycoprotein;
D O I
10.1016/j.lfs.2005.04.025
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Clinical trials evaluating high doses of dextromethorphan hydrobromide (DM) for the treatment of neurological disorders have resulted in numerous adverse events due to the presence of its active metabolite dextrorphan (DX). Since the uptake of drugs in the CNS can be modulated by P-glycoprotein (P-gp) inhibition at the blood-brain barrier (BBB), we propose to determine whether the P-gp inhibitor verapamil can enhance the uptake of DM in the CNS. Rats (n = 42) received an oral dose of DM (20 mg/kg) alone or 15 min after an intravenous dose of verapamil (1 mg/kg). Rats were euthanized at different time points over 12 h, and concentrations of DM and DX (conjugated and unconjugated) were assessed in plasma, brain and spinal cord using a LC-ESI/MS/MS method. Pharmacokinetic parameters were calculated using noncompartmental methods. Verapamil treatments did not affect the biodisposition of DM in plasma. On the other hand, verapamil treatments increased the area under curve of DM in the brain (from 1221 to 2393 ng h/g) and spinal cord (from 1753 to 3221 ng h/g) by approximately 2-fold. The uptake of DX in brain and spinal cord were markedly lower than those of DM and increased by only 15% and 22% following verapamil treatments, respectively. These results suggest that the P-gp inhibitor verapamil can enhance the uptake of DM in the CNS without affecting that of DX. This change is most likely related to an inhibition of P-gp or other transporters located in the BBB since the biodisposition of DM in plasma remained unaffected by verapamil treatments. (c) 2005 Elsevier Inc. All rights reserved.
引用
收藏
页码:2911 / 2926
页数:16
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